Contrast agents or contrast media, are substances that can alter the way in which a region is analyzed in medical imaging. In particular, they are able to change the contrast of an organ, an injury, or any other surrounding structure, to make visible such details that otherwise would be difficult to detect or appreciate.
Contrast agents are primarily used in the radiological or in the nuclear magnetic resonance diagnostic fields. Depending on the field of application, these derivatives present structural features, such as, in the case of molecules useful as contrast agents for X-rays analysis, the presence of one or more atom with high atomic number (e.g. iodine or barium). Iopamidol (N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2S)(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzendicarboxamide) and Iomeprol (N,N′-bis(2,3-di-hydroxypropyl)-5-[(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzendicarboxamide), whose structural formulas are indicated below, are two of the numerous tri-iodinated diagnostic agents, commercially available and widely used for this purpose:

Among the various synthetic procedures known in the art for the preparation of tri-iodinated aromatic derivatives useful in radiology applications, some of said procedures involve the rearrangement of an appropriate tri-iodo phenyl ether precursor to give the desired product, wherein a new amide functional group is obtained throughout a structural rearrangement of the corresponding ether group (such rearrangement is known as a “Smiles rearrangement”, see as a general reference: S. Smiles et al., J. Chem. Soc 1931, 3264).
In particular, in this regard, WO97/05097 describes the preparation of iopamidol via Smiles rearrangement, starting from a given ether intermediate (this latter obtained by a SN2 reaction of a precursor, in a salt form thereof) with a (R)-2-propanamidic derivative in various organic solvents, according to the following scheme:

Said rearrangement is carried out in an alkaline alcohol mixture, typically constituted by methanol in the presence of KOH, at reflux for 2 hours, thus providing iopamidol with an overall yield of the two steps of 56%. Also exemplified in WO97/05097 are (R)-2-propanamidic derivatives in which the leaving group Z, involved in the first condensation step, is a leaving group generally chosen from: tosylate (TsO), mesylate (MsO) and chlorine.
Anelli et al. (Tetrahedron, Vol. 53, No. 34, 1997, pp 11919-11928) describe the preparation of 5-[(2-hydroxyacyl)amino]-2,3,6,-triiodo-1,3-benzendicarboxamidic derivatives, also including iomeprol and iopamidol, by Smiles rearrangement of a suitable ether precursor. In particular, there are described two methods (method A and B) comprising the use of a base, respectively in the presence of water or of an organic solvent, such as DMF. Both methods however lead to the co-formation of side products in varying amounts, due to the competitor reactions of cyclization and/or hydrolysis of the starting substrate. Also, the use of an aqueous solvent in the preparation of iopamidol results in a drastic reduction in the yield, compared to the same reaction when carried out in DMF (17.9% vs 99% of method A vs method B).
It should be noted, finally, that in the case of substances intended for a parenteral use as contrast agents, the final chemical and optical purity are of fundamental importance, as specifically required by the health authorities.
We have now found a new process for the preparation of 5-[(2-hydroxyacyl)amino]-2,4,6-triiodo-1,3-benzendicarboxamidic derivatives, such as iopamidol and iomeprol, via Smiles rearrangement of a suitable tri-iodine ether precursor, by contact of an aqueous solution of said precursor with an anion exchanger solid phase. The process of the present invention, comprising an aqueous solvent system, allows advantageously to carry out the reaction in more favourable conditions, even from the environmental point of view, than the prior art and, even more advantageously, it allows to obtain the final products, useful as contrast agents for example in radiology, with high yields, high degree of optical purity and substantially free of by-products.